[Individualized antifungal therapy in critically ill patients with invasive fungal infection]. / Tratamiento antifúngico individualizado en el paciente crítico con infección fúngica invasora.

Invasive candidiasis (IC) is the most common invasive fungal infection (IFI) affecting critically ill patients, followed by invasive pulmonary aspergillosis (IPA). International guidelines provide different recommendations for a first-line antifungal therapy and, in most of them, echinocandins are considered the first-line treatment for IC, and triazoles are so for the treatment of IPA. However, liposomal amphotericinB (L-AmB) is still considered a second-line therapy for both clinical entities. Although in the last decade the management of IFI has improved, several controversies persist. The antifungal drugs currently available may have a suboptimal activity, or be wrongly used in certain IFI involving critically ill patients. The aim of this review is to analyze when to provide individualized antifungal therapy to critically ill patients suffering from IFI, emphasizing the role of L-AmB. Drug-drug interactions, the clinical status, infectious foci (peritoneal candidiasis is discussed), the fungal species involved, and the need of monitoring the concentration of the antifungal drug in the patient are considered.

Activity of antifungal agents alone and in combination against echinocandin-susceptible and -resistant Candida parapsilosis strains.

BACKGROUND: Candida parapsilosis may acquire resistance to echinocandins, a fact that prompts the search for new therapeutic options. AIMS: The present study aimed to evaluate the in vitro activity of antifungal agents, alone and in combination, against four groups of C. parapsilosis strains: (1) echinocandin-susceptible (ES) clinical isolates (MIC ≤ 2µg/ml), (2) anidulafungin-resistant strains (MIC ≥ 8µg/ml), (3) caspofungin-resistant strains (MIC ≥ 8µg/ml), and (4) micafungin-resistant strains (MIC ≥ 8µg/ml). METHODS: Antifungal interactions were evaluated by a checkerboard micro-dilution method. The determination of the MIC to each drug for every isolate according to the Clinical and Laboratory Standards Institute documents M27 (2017) and M60 (2017) was also done. RESULTS: The echinocandins-resistant (ER) strains showed higher MICs to the tested antifungals than the ES strains, except for amphotericin B, for which the ER groups remained susceptible. CONCLUSIONS: Most combinations showed indifferent interactions. The use of monotherapy still seems to be the best option. As resistance to echinocandins is an emergent phenomenon, further studies are required to provide clearer information on the susceptibility differences between strains to these antifungal agents.

[Invasive aspergillosis in critically ill patients]. / Aspergilosis invasiva en el paciente crítico.

Critically ill patients without severe immunosuppression make up a population in which invasive aspergillosis (IA) has been identified as an emergent pathology. Chronic treatment with corticosteroids, chronic obstructive pulmonary disease, and liver cirrhosis are repeatedly identified risk factors. However, due to the non-specificity of the symptoms and signs in the critical patient, and the relative low diagnostic capacity of the complementary tests, the diagnosis of the IA is a challenge for the specialist in critical care medicine. The application of diagnostic algorithms adapted to critical patients, in whom activation will depend on the isolation of Aspergillus in a respiratory specimen, is the most efficient diagnostic methodology in this population. Among the diagnostic approaches, the determination of galactomannan in bronchoalveolar fluid is the most useful diagnostic test. Once the suspicion is established, treatment should be started as soon as possible. Voriconazole, amphotericin B, and isavuconazole are the most effective treatments. Although voriconazole and amphotericin B are the drugs with the most scientific evidence, they are related with adverse effects and pharmacokinetic difficulties. Therefore, isavuconazole, which has shown high efficacy and safety in other populations, is a potential alternative of great interest for critically ill patients.

Drug susceptibility profile of Candida glabrata clinical isolates from Iran and genetic resistant mechanisms to caspofungin.

BACKGROUND: Candida glabrata is a yeast that can cause hazardous fungal infections with high mortality and drug resistance. AIMS: The aim of this study was to determine the profile of drug susceptibility in clinical isolates of C. glabrata and review the resistance mechanisms to caspofungin. METHODS: A total of 50 C. glabrata clinical isolates from Iran were tested for in vitro susceptibilities to amphotericin B, caspofungin, fluconazole and voriconazole. To investigate the mechanism of resistance to caspofungin, hotspot areas of FKS1 and FKS2 genes were sequenced and gene expression profile was evaluated. RESULTS: All the isolates were susceptible to amphotericin B and caspofungin. Fluconazole resistance was exhibited in four isolates. In addition, only one isolate was resistant to voriconazole. FKS2 with 12 point mutations showed more mutations compared to FKS1 that had only two mutations. All substitutions were synonymous. FKS genes were expressed at comparable levels (no statistical significance) in caspofungin-treated and non-treated cultures. CONCLUSIONS: The silent mutations in the hotspot areas of FKS genes and inconsiderable changes in gene expression were not associated with increased MIC (0.25µg/ml). Other mechanisms of resistance which include mutations outside the hotspot area of FKS genes could be involved in a slight increase of MIC, and they should be identified through complete FKS gene sequencing.

Opciones terapéuticas frente a especies de Candida resistentes a las equinocandinas / Therapeutic options in the management of echinocandin resistant Candida species

Introducción: La infección por levaduras del género Candida representa la causa más común de infecciones fúngicas invasivas. Su alta incidencia y la creciente resistencia frente a los azoles y, recientemente, a las equinocandinas ha generado la necesidad de buscar nuevas alternativas farmacológicas. Esta revisión presenta las principales alternativas farmacológicas en estudio frente a Candida resistente a equinocandinas. Métodos: Se buscó literatura referente al tema en las bases de datos Bireme, Clinical Key, Embase, Cochrane, Lilacs, Pubmed y Scopus. Se incluyeron 15 artículos en esta revisión. Resultados: Se exploran diferentes alternativas, incluyendo el aumento de dosis de las equinocandinas, su combinación con otros medicamentos y nuevos compuestos en estudio. Conclusión: A pesar de que las infecciones por Candida resistente a equinocandinas aún representan un desafío, dos alternativas farmacológicas se presentan como promisorias: la combinación con medicamentos existentes como el diclofenaco y nuevos compuestos que se encuentran actualmente en fase II de estudios clínicos.

Introduction: Candida yeasts infections represent the most common cause of invasive fungal infections. Its high incidence and increasing resistance to azoles and, recently, to echinocandins has generated the need to find new therapeutic options. This review presents the main pharmacological alternatives in research against echinocandins resistant Candida. Methods: A search was conducted in the databases of Bireme, Clinical Key, Embase, Cochrane, Lilacs, Pubmed and Scopus. 15 articles were included in this review. Results: Several alternatives are explored, including increased doses of echinocandins, combination with other drugs and new compounds under study. Conclusion: Although resistant Candida infections still represent a challenge, two pharmacological approaches show promise: The combination with existing medicaments such as diclofenac, and new compounds that are currently in Phase II of clinical trials.

Cambios clínicos y epidemiológicos de candidemias en pacientes adultos desde 2000 a 2013 / Clinical and epidemiological changes of candidemia among adult patients from 2000 to 2013

Background: Invasive Candida spp. infections have been described more frequently. Aim: To characterize the epidemiological data of candidemia in recent years. Methods: A retrospective study of adult patients in a University Hospital in Santiago, Chile, with 1 or more documented episodes of candidemia, from January 2000 to December 2013. Results: One hundred and twenty episodes of candidemia were identified in 120 patients, annual incidence of 0.4 cases per 1000 discharges, 53.3% were male patients, 58.3% > 60 years, 77,5% had at least one co-morbidity. Candida albicans was the species most frequently identified 55%, followed by C. glabrata 18.3%, C. tropicalis 11.7% and C. parapsilosis 9.2%. Comparing 2000-2006 vs 2007-2013, increased the frequency of C. parapsilosis among non-albicans and echinocandins prescription. Patients with C. albicans showed higher APACHE-II, more requirement for invasive mechanical ventilation, greater association with CVC, and shorter incubation time compared with non-albicans species. The 30-day mortality was 31.7%. Conclusions: During this 14-years period we observed that C. albicans was the predominant specie and more recently a change among C. non-albicans increasing C. parapsilosis and decreasing C. glabrata 30-days and attributable mortality decreased together with more echinocandins prescription.

Introducción: Las infecciones invasoras por Candida spp. se describen cada vez con mayor frecuencia. Objetivo: Precisar datos epidemiológicos de candidemia en nuestro hospital en los últimos años. Metodología: Estudio retrospectivo de pacientes adultos de un hospital universitario en Santiago, Chile, con un o más episodios de candidemia, acaecidas desde enero de 2000 a diciembre de 2013. Resultados: Se identificaron 120 episodios de candidemia, incidencia anual 0,4 casos x 1.000 egresos, 53,3% pacientes masculinos, 58,3% > 60 años y 77,5% presentaban al menos una co-morbilidad. Candida albicans fue la especie más frecuente (55%), seguida por C. glabrata (18,3%), C. tropicalis (11,7%) y C. parapsilosis (9,2%). Los tiempos de incubación e identificación fueron más prolongados para C. glabrata. Al comparar el período 2000-2006 vs 2007-2013, aumentó la frecuencia de C. parapsilosis entre las C. no-albicans y el uso de equinocandinas. Los pacientes con C. albicans presentaban puntaje APACHE-II más elevado, mayor requerimiento de ventilación mecánica invasora, mayor asociación a CVC y menor tiempo de incubación respecto C. no-albicans. La mortalidad a 30 días fue de 31,7%. Conclusiones: Durante este período de 14 años observamos predominio de C. albicans y en el período reciente incremento de C. parapsilosis con disminución de C. glabrata, una disminución de mortalidad global y atribuible junto a mayor uso de equinocandinas.

[Echinocandins: Applied pharmacology]. / Equinocandinas: aspectos aplicados de la farmacología.

The echinocandins share pharmacodynamic properties, although there are some interesting differences in their pharmacokinetic behaviour in the clinical practice. They are not absorbed by the oral route. They have a somewhat special distribution in the organism, as some of them can reach high intracellular concentrations while, with some others, the concentration is reduced. They are highly bound to plasma proteins, thus it is recommended to administer a loading dose for anidulafungin and caspofungin, although this procedure is not yet clear with micafungin. Echinocandins are excreted via a non-microsomal metabolism, so the urinary concentration is very low. Some carrier proteins that take part in the biliary clearance process are probably involved in the interactions described with caspofungin and micafungin. These two drugs must be used with caution in patients with severely impaired hepatic function, while all of them can be used without special precautions when there is renal impairment or the patient requires renal replacement therapy.

Antifungal stewardship in a tertiary hospital.

BACKGROUND: The inappropriate use of antifungals is an important health problem related to increasing adverse effects, unnecessary cost and promotion of resistant and emerging fungal infections. Despite its relevance, many health institutions assign few resources to improve prescribing practices. AIMS: To evaluate the efficiency of an antifungal stewardship programme (ASP) centered on restricted antifungal agents. METHODS: The main activity during the eight-month study was to perform a programmed review of restricted antifungals (lipid formulations of amphotericin B, echinocandins and voriconazole) prescribed in hospitalized patients. In the case of amendable antifungal treatment, a recommendation was included in the electronic medical record. RESULTS: A total of 280 antifungal prescriptions for 262 patients were revised during the study period. The indications were prophylactic in 85 cases (30.4%), pre-emptive in 10 cases (3.5%), empiric in 122 cases (43.6%), and directed in 63 cases (22.5%). A total of 70 prescriptions (25%) in 61 patients were considered to be amendable. In most of these cases, treatment could have been reduced considering the patient's clinical improvement and microbiological results. The most common advice was antifungals change (70%), antifungal withdrawal (21%), removal of one antifungal drug in cases of combined therapy (7%), and switching to oral route (1%). Proposed recommendations were addressed in 28 cases (40%). There was no significant difference in adherence with respect to the type of recommendation (p=0.554). There was a 42% lower use of antifungals during the period of the study compared to that observed during a similar previous period. Mortality among patients who were treated according to the recommendations of the ASP was 17% and in whom treatment was not modified it was 30% (p=0.393). CONCLUSIONS: ASPs centered on hospitalized patients may be an efficient strategy to ameliorate antifungal use in hospitals.

Tratamiento exitoso de una mucormicosis rinocerebral persistente en un paciente pediátrico durante el debut de una leucemia aguda / Successful treatment of a persistent rhino-cerebral mucormycosis in a pediatric patient with a debut of acute lymphoblastic leukemia

The fungi of the order Mucorales cause mucormycosis, which usually presents as an invasive fungal disease with rapid angioinvasion in immunocompromised patients. Rhinocerebral is the most common presentation. The lipid formulations of amphotericin B are used as primary treatment in invasive mucormycosis; the combined use of posaconazole could allow a reduction in the dose of amphotericin B improving tolerance and adherence to treatment. Caspofungin and amphotericin B association has been shown to be synergistic in vitro and effective in murine models. We present the case of a preschool patient that during the debut of acute lymphoblastic leukemia developed a rhinocerebral mucormycosis successfully responding to antifungal treatment with the combination of liposomal amphotericin and caspofungin.

Los hongos del orden Mucorales causan la mucormicosis, que se presenta habitualmente como una enfermedad fúngica invasora con rápida angioinvasión en pacientes inmunocomprometidos. La presentación rino-cerebral es la más frecuente. Las formulaciones lipídicas de anfotericina B se usan como tratamiento primario en las mucormicosis invasoras; el uso combinado de posaconazol podría permitir reducir la dosis de anfotericina B generando una mejor tolerancia y adherencia al tratamiento. La asociación de caspofungina con anfotericina ha demostrado acción sinérgica in vitro y eficacia en modelos murinos. Se presenta el caso de una niña preescolar que durante el debut de una leucemia linfoblástica aguda evolucionó con una mucormicosis rino-cerebral persistente, que respondió en forma exitosa al tratamiento antifúngico combinado de anfotericina liposomal y caspofungina.

Indicación de nuevos antimicóticos en pacientes con candidiasis invasiva / Prescription of new antifungal drugs in patients with invasive candidiasis

Las infecciones micóticas invasivas han alcanzado tal importante diseminación en las unidades de cuidados intensivos, que hoy constituyen la cuarta causa de infecciones adquiridas en este servicio, con una mortalidad de hasta 50 por ciento. La inmunodepresión propia del paciente en estado crítico, unido a la aplicación de determinados procedimientos traumáticos -- catéteres, sondas, endoscopias, ventilación, intervenciones quirúrgicas abdominales, nutrición parenteral, entre otros --, predisponen a la infección. Al respecto, se está empleando una gama de nuevos antimicóticos (triazoles y equiniocandinas) en el tratamiento de pacientes con micosis invasivas, sobre la base de que la creación de protocolos terapéuticos puede disminuir el índice de mortalidad por dichas afecciones(AU)

The invasive fungal infections have reached such an important dissemination in the intensive care units that today they constitute the fourth cause of acquired infections in this service, with a mortality of up to 50 percent. The immunodepression characteristic of the patient in critical state, together to the application of certain traumatic procedures -- catheters, probes, endoscopies, ventilation, abdominal surgical interventions, parenteral nutrition, among other --, predispose to the infection. In this respect, a range of new antifungal drugs are being used (triazoles and equiniocandines) in the treatment of patients with invasive mycosis, on the base that the creation of therapeutic protocols can decrease the mortality index caused by these disorders(AU)

Equinocandinas / Echinocandins

The echinocandins, caspofugin, micafungin, and anidulafungin, are lipopeptides that inhibit fungal growth by binding to β - (1.3) d glucan synthase. This enzyme is responsible for the formation of the peptidoglycan cell wall, and it is essential in fungi such as Candida spp, but less important in the case of Aspergillus and Fusarium species. We review the history, pharmacology and clinical trials that have showed clinical efficacy similar to amphotericin B for the management of fungal infections such as candidemia, invasive candidiasis and aspergillosis, even in cases refractory to initial treatment. These drugs have less toxicity and discontinuation is uncommonly required. Despite similar spectrum and tolerability, there are several pharmacological differences. Only a few clinical trials compare the clinical efficacy between them and their clinical application cannot be generalized. However, the echinocandins have demonstrated clinical efficacy in patients with invasive candidiasis and in others forms of systemic mycoses.

Las equinocandinas -caspofugina, micafungina y ani-dulafungina- son lipopéptidos que inhiben el crecimiento fúngico al unirse a la β-(1,3) d glucano sintetasa, enzima esencial para la síntesis en la pared celular de hongos como Candida spp, y menos importante en el caso de especies de Aspergillus y Fusarium. Se revisa la historia, farmacología y los diferentes ensayos clínicos que han evidenciado similar eficacia clínica a la de anfotericina B para el manejo de infecciones micóticas como candidemia, candidiasis invasora y aspergilosis, inclusive en casos refractarios al manejo inicial. Estos medicamentos tienen menor toxicidad y en pocos casos hay necesidad de retiro del tratamiento. Dado su espectro y tolerabilidad similar, su farmacología permite diferenciarlas. Se dispone de información limitada de estudios clínicos que las comparen entre ellas, limitando la extrapolación de la información a todo el grupo. Sin embargo, presentan eficacia clínica comprobada en pacientes con varias micosis invasoras.

Candidiasis invasoras en el paciente crítico adulto / Invasive candidiasis in critically ill adult patient

Las infecciones invasoras por Candida spp, representan una patología relevante en los pacientes críticos. Para su oportuno diagnóstico es necesaria una elevada sospecha clinica, tomando en consideración el cuadro clinico y la presencia de factores de riesgo. Pese a la incorporación de nuevos fármacos al arsenal terapéutico durante la última década, mantiene una elevada mortalidad. Las claves para mejorar los desenlaces clínicos en estos pacientes son el empleo de una terapia precoz, eficaz y que permita la cobertura de distintas especies de Candida: C albicans y no albicans. Recientes guías internacionales sugieren la terapia empírica con equinocandinas ante la sospecha de candidiasis invasora en esta población de pacientes. Este grupo de fármacos ha documentado adecuada eficacia clínica y seguridad en estos pacientes. Se espera que la incorporación de nuevas equinocandinas al mercado aminore sus costos y mejore el acceso a este grupo de fármacos.

Invasive infections by Candida strains are a relevant pathology in critically ill patients. Candida should be considered where a high risk of infection is present for a critical early diagnosis. Despite the incorporation of new drugs in the therapeutic armamentarium over the last decade, mortality remains high. The key in improving clinical outcomes of these patients are the use of early effective therapies that offer coverage against different strains of Candida: C. albicans and non-albicans. Recent international guidelines suggest empiric therapy with echinocandins in suspected invasive candidiasis in this patient population. This group of drugs adequately documented clinical efficacy and safe use in these patients. The emergence of new echinocandins could improve access to these drugs by reducing their cost.

Expresiones cutáneas de candidiasis sistémica en pacientes inmunosuprimidos / Cutaneous expression of systemic candidiasis in immunosuppressed patients

La candidiasis sistémica constituye una importante causa de morbimortalidad en pacientes internados en centros de alta complejidad. Las expresiones cutáneas de la infección son múltiples y se observan en un pequeño porcentaje de pacientes. Se presentan cinco casos de candidiasis sistémica con compromiso cutáneo en pacientes inmunosuprimidos: un paciente trasplantado de médula ósea, dos pacientes con leucemia mieloide aguda, un caso de sepsis bacteriana y un paciente con linfoma linfocítico. Todos los pacientes presentaron fiebre persistente y lesiones cutáneas que se biopsiaron para estudio histológico y cultivo. La histopatología mostró seudohifas en tres de los casos. En los cultivos de piel se identificó a Candida tropicalis, Candida Krusei y Candida albicans en dos pacientes. El incremento de cepas resistentes hace necesario el empleo de nuevos antifúngicos como las equinocandinas para el tratamiento de esta entidad.

Systemic candidiasis is a signifi cant cause of morbidity and mortality in immunosuppressed hospitalized patients. Skin signs of systemic candi-diasis are numerous although they can be observed in a small percent-age of patients. We report fi ve cases of systemic candidiasis with cutaneous manifestations in immunosuppressed patients: one case of bone- marrow transplantation, two patients with acute myeloid leukaemia, one with bacterial sepsis and one patient with lymphocitic lymphoma. The patients presented persistent fever and cutaneous lesions. Skin biopsy for histopathological study and cultures were carried out. The histological examination showed yeasts in three of the cases. Skin culture revealed: Candida tropicalis, Candida krusei and Candida albicansin two cases. Due to the increase of resistant species new drugs such as echinocandins are currently available for the treatment of this entity.

Antimicóticos de uso sistémico: ¿con qué opciones terapéuticas contamos? / Systemic antifungals: which therapeutic options do we have?

La prevalencia de infecciones fúngicas invasivas ha aumentado en las últimas tres décadas debido al aumento de huéspedes inmunocomprometidos. Durante muchos años la anfotericina B y la flucitosina fueron los únicos antifúngicos disponibles para el tratamiento de estas micosis. Afortunadamente, en la última década el arsenal de antifúngicos se ha ampliado, lo que provee nuevas alternativas terapéuticas para los pacientes afectados. El objetivo de este artículo es resumir las características farmacológicas de los antifúngicos sistémicos tradicionales (anfotericina. flucitosina, itraconazol y fluconazol) y de los agentes antimicóticos de uso reciente: los nuevos triazoles (voriconazol, posaconazol) y las equinocandinas (caspofungina. micafungina y anidulofungina).

The prevalence of invasive fungal infections has increased over the past three decades owing to the increasing numbers of immunocompromised hosts. For many years, amphotericin Band flucytosine were the only available antifungal agents for invasive fungal infections. Fortunately, the antifungal drugs has increased, providing new therapeutic options for these patients. The purpose of this article is to summarize the pharmacologic profile of traditional antifungal drugs (amphotericin, flucytosine, itraconazole, fluconazole) as well as the ones recently licensed: the new triazoles (voriconazole, posaconazole) and the echinocandins (caspofungin, micafungin, anidulafungin).